KR890000787B1 - Process for oreoaring injection containing cephalosporin derivatives - Google Patents

Abstract

Cephalosporin was prepd. for injection. Thus, 1.0g 7β -[2-(2 - aminothiazol-4-yl)-(z)-2-methoxyiminoacetamide -3-[(1-methyl- 1Htetrazol-5-yl)thiomethyl ceph-3-em-4-carboxylate [I in 18ml H2O was treated with 2ml 10% HCl to give 0.73g [I .1/2HCl.

Description

Method for preparing injectable or external preparation of cephalosporin derivative components

1 is a powder X-ray dilution obtained in Example 1 (Cuka, 40KV, 45mA),

2 shows the infrared absorption specification (KBr) of the target product obtained in Example 1. FIG.

The present invention provides 7 β [2- (2-aminothiazol-4-yl)-(z) -2-methoxyiminoacetamide] sef-3-[(1-methyl-1H-tetrazol-5 -Il) thiomethyl] sef-3-m-4-carboxylic acid (hereinafter abbreviated as compound (I)) of 1 molecule of HCl or HBr 1/2 molecule of the main component of the crystalline salt for injection or preparation of an external preparation It is about. Compound (I) has excellent antimicrobial activity [Ochiai, Angei, Morimodo, Okara, Matsushidazer: Chemical & Permeable Bulletin (chem, pharm, Bull), 25,3115 (1977)], In general, cephalosporin derivatives are compounds that are unstable against heat, light, acid, alkali, etc., and their handling (isolation, tablet preservation, etc.) requires careful attention. When reacted with HCI or HBr, a crystalline salt of one molecule of Compound (I) with one half of HCI or HBr is obtained, and the crystalline salt has excellent handling properties, and is particularly resistant to long-term storage. The present invention was completed based on this finding. That is, this invention relates to the manufacturing method of the crystalline salt with 1 molecule of HCI or HBr2 molecule of compound (I) characterized by making compound (I) react with HCI or HBr. A crystalline salt of one molecule of compound (I) of the present invention and one molecule of HCI or HBr is prepared by reacting compound (I) with HCI or HBr.

Compound (I), which is a raw material, may be used as it is or according to a conventional method, for example, a salt with an alkali metal (sodium, potassium, lithium, etc.), a salt with an alkali earth metal (calcium, magnesium, etc.), an organic base (triethylamine, It can also be used by inducing it with a salt with diethylamine, etc., and a liquid-decomposable ester (silyl ester etc.), and a sodium salt is used conveniently among these. The other raw material, HCI or HBr, may be used in gaseous form, but usually it is convenient to dissolve it in a solvent such as water, and among these, hydrochloric acid (hydrochloric acid) and hydrochloric acid are frequently used. The reaction is usually carried out in a solvent. It is most preferable to use water as the solvent, but a mixed solvent of water and an organic solvent can also be used. The organic solvent includes, for example, for methanol, ethanol, n- propanol, isopropanol, etc. of C _{1 ~ 5} alcohols, such as acetone, methyl ethyl ketone, etc. C _{3 ~ 9} ketone of example, tetrahydrofuran, dioxane Solvents, such as ether and acetonitrile, which dissolve in water can be used, and ethanol and acetone are particularly preferable. The amount of HCI or HBr used varies depending on the type of raw material used, the type of solvent, and the like. Generally, 1/2 mole or more is used per mole of compound (I), and usually 10 moles or less. Specifically, when the compound (I) of the raw material is used as it is, with respect to 1 mol of the raw material, HCI or HBr is used in a ratio of 0.5 to 10 moles, preferably 1 to 5 moles, and the compound (I) is used as an alkali metal salt or alkali. In the case of induction into an earth metal salt or an organic base salt, it is preferable to add 1-2 mol of HCI or HBr in order to change the raw material into a glass state. The reaction temperature is usually carried out at a temperature range of 0 to 40 ° C, preferably 10 to 30 ° C. The reaction time varies depending on the purity of the raw materials to be used and the kind of impurities, for example, when raw materials having a purity of 80% or more are used for 30 minutes to 24 hours, preferably 30 minutes to 16 hours. The reaction product is collected by, for example, filtration, centrifugation, or the like. Depending on the amount of HCI or HBr used, the type of solvent or the amount used, crystalline salts of one molecule of compound (I) and one molecule of HCI or HBr may be produced. Contact with water, for example, water or an organic solvent By washing as a mixture, the target object is obtained easily. Specifically, the crystalline salt of one molecule of compound (I) and one HCI or one HBr molecule obtained by filtration of the reaction product is washed with a water of 5 to 50 culture or a mixture of water and an organic solvent. Or the target object is obtained when it is left for 5 minutes to 2 hours or stirred in 0 to 30 degreeC in the same amount of water or a mixture of water and an organic solvent. This is because the crystalline salt of one compound of compound (I) and one molecule of HCI or HBr is an acid salt of weak base, so that when contacted with excess water or a mixture of water and an organic solvent, it dissociates into compound (I) and HCI or HBr once. Then, it is considered to convert into the stable target object.

The crystalline salt of thus obtained compound (I) and HCI or HBr 1/2 molecule may contain water or an organic solvent as a crystalline solvent or an adhesion solvent, and these are also included in the object of the present application. At this time, the amount of water is usually 3% or less, and the smaller the water content, the better the stability. For example, the moisture content can be adjusted by drying with wind or drying under a reduced pressure, for example, by drying with a dehydrating agent such as silica gel or phosphoric anhydride, and the water content of 0.05 to 1% is particularly preferably 0.1 to 0.5%. Moreover, when the organic solvent is contained, you may remove it, for example by contacting and absorbing water vapor as needed.

It was confirmed that the target compound thus obtained had half of HCl or HBr with respect to one molecule of Compound (I) in the elemental analysis value, and it was confirmed that it was crystalline by a microscope, a polarizing microscope, an X-ray dilution figure, or the like. do. In addition, in the infrared absorption spectra, sharp peaks different from amorphous powders are recognized. The crystalline salt of one molecule of such compound (I) with one molecule of HCI or HBr is very stable and has many advantages in handling of production, isolation, purification, storage and the like.

The crystalline salt of the present invention can be used as an oral preparation as it is, or dissolved in distilled water with non-toxic alkali or alkali salts such as sodium hydrogen carbonate, sodium carbonate, trisodium phosphate, etc. to a desired pH, ionic form, and ionic strength. It may be adjusted and used as an injection or external preparation. For example, an aqueous solution in which 3/4 mol of sodium carbonate is dissolved in 1 mole of a crystalline salt of a target can be used as an external disinfectant such as, for example, a surgical instrument, a hospital room, a disinfectant for drinking water, and the like. Gram-positive bacteria (eg, Staphylococcus, Oureus staphyococcus aureus, etc.) or Gram-positive bacteria (eg, Escherichia coli, Crevji) for mixed race animals such as rats, dogs, etc. As a medicine for infectious diseases caused by klebsiella pneumoniae, Proteus, proteus vulgaris, etc., it is administered by intramuscular injection or intravenous injection. 100r / ml aqueous solution can be prepared and sprayed on surgical instruments, and it can be used for urinary tract infection caused by Escherichia coli infection in humans or mice. In this case, intravenous injection of about 2.5 to 25 mg / kg in three divided doses per day, in the form of a solvent-free product, and these preparations may be used as crystalline salts of compounds (I) and HCI or HBr and non-toxic alkalis or The alkali salts are preferably stored alone or as a mixture, in some cases under inert gas filling or under reduced pressure, and dissolved in sterile distilled water or the like when used.

Reference Example 1

Antimicrobial activity of target product converted into solventless

(MIC)

Antibacterial Spectrum (Agar Dilution Method)

Star Pyrococcus Oureus FDA 209P 1.56mcg / ml

Star PyrococcusOureus 1840 3.13mcg / ml

Ashley Collie-NIHJ JC-2 0.1mcg / ml

Ashley Collie 0-111 0.024mcg / ml

Ashley Collie T-7 0.39mcg / ml

It is DT 0.024mcg / ml to crevgeella pneumoniae

Proteus bulgari IFO 3988 0.024mcg / ml

Proteus morganini IFO 3168 0.1mcg / ml

Proteus mirabills (Proteus mirabills) GN 4359 0.05mcg / ml

0.012 mcg/mlProteus rettgeri TN 336O

0.012 mcg / ml

Citrobacter freundii GN 1706 0.20mcg / ml

Reference Example 2

Aseptic mixture of 1 g of compound (I), 250 g (titer) of crystalline salt for 2 minutes of HCI, and 42.7 g of sterile, dust-free sodium carbonate, and 500 mg (titer) in an aseptic volume of 12 ml After filling in the quotient, it is sealed as a stopper in a vacuum at 50 mmHg. When 2 ml of distilled water is added and dissolved, it becomes an injection solution.

Reference Example 3

Aseptically mix 500 g (titer) of crystalline salt of 1 compound of compound (I) with 1/2 of HCl and 116.6 g of sterile and inert sodium carbonate, and fill it with 1,000 mg (titer) lot in a 28 ml sterile vial. It is then sealed as a stopper in a vacuum at 50 mmHg. When 2 ml of distilled water is added and dissolved, it becomes an injection solution. In addition, the crystalline salt of one molecule of the compound (I) of the present invention and one molecule of HCI or HBr half is 2-aminothiazole type and 2-iminothiazoline in the 2-aminothiazol-4-yl group. It is thought that it may take the form of intervariable structures of the forms. In the present invention, a dimer is included, but 2-aminothiazole type is indicated in the specification.

Example 1

7β-[-2- (2-aminothiazol-4-yl)-(z) -2-methoxyiminoacetamide] -3-[(1-methyl-1H-tetrazol-5-yl) thio 5.0 g of sodium salt of methyl] sef-3-m-4-carboxylic acid is dissolved in 3.31 of water, and 0.31 of 10% HCl water is added dropwise while stirring at an internal temperature of 25.5 占 폚. During dropping, the carboxylic acid precipitates as a colorless precipitate, and then dissolves. Stirring this solution as it is for 1 hour to precipitate colorless crystals. The crystals were filtered out (the pH of the filtrate was 1.1), and after washing with water, the water was sufficiently drained and dried under reduced pressure (about 1 mmHg) for 5 hours using a vacuum pump at 25 ° C in the presence of silica gel blue in a desiccator. When the vacuum pump is stopped and left under reduced pressure for 24 hours, the carboxylic acid. 154.5 g of 1/2 hydrochloride are obtained.

Elemental analysis value: C ₁₆ H ₁₇ N ₉ O ₅ S ₃ 1/2 HCl 1/2 H ₂ O

Calculated value: C: 35.67, H: 3.46, N: 24.40, S: 17.85, C1: 3.29

Found: C: 35.78, H: 3.41, N: 23.46, S: 17.88, C1: 3.46

Moisture measured value 2.1% (calculated value 1.7%) by Kahl Fischer (K.F.) method

NMR (90 MHz in DMSO-d ₆ ) δ: 3.54, 3.79 (1H each, doublet, J = 18 Hz), 3.89 (3H, singlelet), 3.91 (3H, singlelet ), 4.18, 4.36 (1H each, doublet, J = 13 Hz), 5.09 (1H, doublet, J = SHz), 5.71 (1H, quarter, J = 5.9 Hz ), 6.80 (1H, singlet, 9.65 (1H, doublet, J = 9 Hz)

IR (KBr) cm ^-1 : 1780 (β-lactam)

This product shows crystallinity as the powder X-ray dilution degree as shown in FIG. 1, and the dilution line d is 9.1 kV, 6.7 kV, 6.5 kV, 5.0 kV, 4.1 kV, 3.9 kV, 3.7 kV, 3.5 kV, 3.4 kV , 3.3Å, 3.2Å

A part of the product was dried at 25 ° C. on P ₂ O ₅ under a reduced pressure (about 1 mmHg) using a vacuum pump for 5 hours, and the pump was stopped for 16 hours while maintaining the reduced pressure. Law). The powder X-ray dichroism and IR spectra of this compound are consistent with that of the compound of 2.1% of moisture. The residual rate when this compound was left at 40 degreeC for 1 month was 98% or more.

Example 2

7β- [2- (2-aminothiazol-4-yl)-(z) -2-methoxyiminoacetamide] -3- [(1-methyl-1H-tetrazol-5-yl) thiomethyl ] 1.00 g of cef-3-em-4-carboxylic acid is suspended in 18 ml of water, and 2 ml of 10% HCl water is added with stirring as room temperature (25 ° C). When the obtained solution is stirred as it is for 30 minutes, colorless crystals are precipitated. The crystals are filtered off, washed with water and dried in the air to yield 0.73 g of the above-mentioned carboxylic acid 1/2 hydrochloride (water 3.2% (K.F. method)).

The powder X-ray dilution and the IR stacking frame of this product are consistent with that of the compound obtained in Example 1.

Example 3

7- [2- (2-aminothiazol-4-yl)-(z) -2-methoxyiminoacetamide] -3-[(1-methyl-1H-tetrazol-5-yl) thiomethyl ] Dissolve in a mixed solvent of 0.05 g acetone 5 ml of acetone-3-m-4-carboxylic acid and 1 ml of water, and stir at room temperature (23 ° C.), add 0.15 ml of 10% HCl water. After stirring for 1.5 hours, the precipitated colorless crystals were filtered off, washed with acetone, and dried under reduced pressure (about 1 mmHg) at room temperature on P ₂ O ₅ for about 3 hours. 0.23 g of 1/2 hydrochloride [water, 1.8% (KF method)] is obtained.

Elemental analysis value: C ₁₆ H ₁₇ N ₉ 0 ₅ S ₃ 1/2 HCl 1/2 H ₂ O1 / 6 (CH ₃ ) ₂ CO

Calculated value: C: 36.13, H: 3.58, N: 22.98, S: 17.53, C1: 3.23

Found: C: 36.51, H: 3.41, N: 23.35, S: 17.51, C1: 2.81

The NMR stack of the product showed that it contained 1/6 moles of acetone. The powder X-ray dilution figure and the IR specification of the present product are consistent with those of the compound obtained in Example 1.

Example 4

7β-[-2- (2-aminothiazol-4-yl)-(z) -2-methoxyiminoacetamide] -3-[(1-methyl-1H-tetrazol-5-yl) thio 0.50 g of a sodium salt of methyl] sef-3-m-4-carboxylic acid is dissolved in 10 ml of water, stirred at room temperature (23 ° C.) and 0.3 ml of 48% HBr water is added. A small amount of precipitated syrup-like material is filtered off, and the filtrate is stirred for 2 hours at room temperature to give colorless crystals. The crystals were filtered off and dried under reduced pressure (about 1 mmHg) at room temperature on P ₂ O ₅ after washing with water to yield 0.27 g of carboxylic acid and 1/2 embrittlement hydrochloride (0.3% of water (KF method)).

Elemental analysis _{values: C 16 H 17 N 9 0} 5 S 3 · 1/2 HBr

Calculated value: C; 34.81, H; 3.20, N; 22.84, Br; 7.24

Found: C; 34.71, H; 3.28, N; 22.82, Br; 6.90 IR (KBr) CM ^-1 : 1780 (β-lactam)

This product exhibits crystallinity in powder X-ray dilution.

Example 5

7β- [2- (2-aminothiazol-4-yl)-(z) -2-methoxyiminoacetamide] -3-[(1-methyl-1H-tetrazol-5-yl) thiomethyl ] 0.50 g of cef-3-em-4-carboxylic acid is suspended in 20 ml of water and 0.4 ml of 48% HBr water is added while stirring at room temperature (23 ° C). Filter a small amount of insoluble portion and stir the filtrate at room temperature (23 ° C.) for 16 hours. Precipitate colorless crystals, and after washing with water, drying under reduced pressure (about 1 mmHg) for about 7 hours at room temperature on P ₂ O ₅ , 0.4 g of the carboxylic acid and 1/2 embrittlement hydrochloride (water 0.5% (KF method)]. Is obtained.

Elemental analysis _{values: C 16 H 17 N 9 0} 5 S 3 · 1/2 HBr

Calculated value: C; 34.81, H; 3.20, N; 22.84, Br; 7.24

Found: C; 34.46, H; 3.31, N; 22.60, Br; 7.39

The powder X-ray dilution figure and the IR specification of the present product are consistent with those of the compound obtained in Example 4.

Example 6

7β- [2- (2-aminothiazol-4-yl)-(z) -2-methoxyiminoacetamide] -3-[(1-methyl-1H-tetrazol-5-yl) thiomethyl ] 78.5 g of ceft-3-em-4-carboxylic acid is suspended in 720 ml of acetone, and 72 ml of water is added to dissolve while stirring under cooling (5 ° C). The solution was filtered using celite and washed with acetone (65 mL) -water (3 mL) as a mixed solvent. Combine the filtrate and the tax solution, add 23 ml of 12N hydrochloric acid while stirring under cooling (5 ° C), stir for 1.5 hours, remove the cooling unit, and stir again for 1.5 hours. Precipitated colorless crystals were filtered with a glass filter and washed with 500 ml of acetone. Humidification nitrogen, gas rolls obtained through water-filled bottles, 1.9 l 1 min-3.3 l. It is made to pass through this crystal layer for 10 hours at a rate of 1 minute. 65.0 g of the carboxylic acid monohydrochloride was obtained by drying the crystal (part of the crystal and measuring water by K.F. method, which was 8.9%) in the presence of silica gel blue cow in a desiccator.

Elemental analysis _{values: C 16 H 17 N 9 0} 5 S 3 · HCl · 1.5 H 2 O

Calculated value: C; 38.42, H; 3.68, N; 21.92, S; 16.73, C1; 6.17

Found: C; 33.59, H; 3.56, N; 22.16, S; 16.79, C1; 5.94

This product contains 4.6% water (4.7% K.F. method, calculated value 4.7%) and 110 ppm acetone.

NMR (90 MHz, in DMSO-d ₆ ) δ: 3.57, 3.81 (1H each, doublet, J = 18 Hz), 3.93 (6H, singlet, 4.19, 4.38 (1H each, doublet) (doublet), J = 13 Hz, 5.12 (1H, doublet, J = 5 Hz), 5.73 (1H, quarter, J = 5.9 Hz), 6.90 (1H, singlet), 9.78 (1H, doublet, J = 5 Hz, IR (KBr) cm ^-1 ; 1770 (β-lactam))

This product exhibits crystallinity in powder x-ray dilution. 0.02 g of carboxylic acid monohydrochloride obtained in (2) and (1) is suspended in 2 ml of water, and stirred at room temperature (26 ° C) for 10 minutes (the change in crystal form is observed during stirring). The resultant crystals are filtered off and washed with water, and dried under reduced pressure (about 1 mmHg) on P ₂ O ₅ for about 5 hours to obtain 0.17 g of the carboxylic acid and 1/2 hydrochloride (0.9% of water (KF method)).

Elemental analysis _{values: C 16 H 17 N 9 0} 5 S 3 · 1 / 2HCl · 1/4 H 2 O

Calculated value: C; 35.97, H: 3.40, N: 23.59, C1: 3.32

Found: C; 35.95, H: 3.11, N: 23.49, C1: 3.08

This product coincides with that obtained in Example 1 in the powder X-ray dilution type and the IR specification.

Claims (1)

(i) (a) 7β- [2- (2-aminothiazol-4-yl)-(z) -2-methoxyiminoacetamide] -3-[(1-methyl-1H-tetrazol- A mixed agent obtained by mixing a crystalline salt of 5-yl) thiomethyl] sef-3-m-4-carboxylic acid with HCl or HBr half molecule and (b) Na ₂ CO ₃ or NaHCO ₃ and (ii) filling and sealing the vial under reduced pressure.

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